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Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male who was carefully monitored for more than 9 years after allogeneic CCR5Δ32/Δ32 HSCT performed for acute myeloid leukemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridization assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5Δ32/Δ32 HSCT.

Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Dusseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings The study included 7792 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p

Persistence of minimal residual disease (MRD) after induction/consolidation therapy in acute lymphoblastic leukemia is the leading cause of relapse. The GMALL 07/2003 study used MRD detection by real-time quantitative polymerase chain reaction of clonal immune gene rearrangements with 1 × 10−4 as discriminating cutoff: levels ≥1 × 10−4 define molecular failure and MRD-negativity with an assay sensitivity of at least 1 × 10−4 defining complete molecular response. The clinical relevance of MRD results not fitting into these categories is unclear and termed “molecular not evaluable” (MolNE) toward MRD-based treatment decisions. Within the GMALL 07/03 study, 1019 consecutive bone marrow samples after first consolidation were evaluated for MRD. Patients with complete molecular response had significantly better outcome (5-year overall survival [OS] = 85% ± 2%, n = 603; 5-year disease-free survival [DFS] = 73% ± 2%, n = 599) compared with patients with molecular failure (5-year OS = 40% ± 3%, n = 238; 5-year DFS = 29% ± 3%, n = 208), with patients with MolNE in between (5-year OS = 66% ± 4%; 5-year DFS = 52% ± 4%, n = 178). Of MolNE samples reanalyzed using next-generation sequencing (NGS), patients with undetectable NGS-MRD (n = 44; 5-year OS = 88% ± 5%, 5-year DFS = 70% ± 7%) had significantly better outcome than those with positive NGS-MRD (n = 42; 5-year OS = 37% ± 8%; 5-year DFS = 33% ± 8%). MolNE MRD results not just are borderline values with questionable relevance but also form an intermediate-risk group, assignment of which can be further improved by NGS.

Thrombocytopenia at diagnosis and platelet drop within the first 6 months have an adverse effect on prognosis of MDS patients. We therefore were interested in the association and impact on prognosis of morphologic findings of megakaryocytes and platelets with platelet count at diagnosis, bleeding complications, and the drop of platelets during the course of disease. This retrospective analysis was based on 334 MDS patients from the Duesseldorf MDS registry that were followed up for blood counts, bleeding, transfusion dependency, and AML evolution and correlated with morphology of the megakaryocytes and platelets. Thrombocytopenia was found more frequently in higher risk MDS and was associated with hypocellularity of the megakaryocytes in the bone marrow. Signs of bleeding were present at diagnosis in 14% and occurred during the disease in 48% of all MDS patients. Death due to bleeding was ranked third behind infections and AML. A decrement of platelets during the first 6 months was associated with an inferior overall survival of 21 vs. 49 months and with a higher cumulative 2-year AML rate of 22.2% vs. 8.3% (p = 0.001). In a multivariate analysis, besides bone marrow blasts and karyotype, decreasing platelets were also associated with an inferior outcome. Signs of bleeding are present in a relevant number of MDS patients and account for significant morbidity and mortality in MDS. We could demonstrate the prognostic importance of decreasing platelets during the course of disease in all MDS patients, identifying patients at higher risk for death or AML progression.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell diseases characterized by cell dysplasia, ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). The median age of 75 years at diagnosis is associated with the presence of comorbidities, which preclude intensive therapies like allogeneic hematopoietic stem cell transplantation in most MDS patients. Risk stratification using the (Revised) International Prognostic Scoring System (IPSS/IPSS-R) is necessary to plan individualized treatment.Luspatercept (ACE-536), a specific activin receptor fusion protein, promotes late-stage erythropoiesis. Two clinical trials, PACE-MDS (phase 2) and MEDALIST (phase 3), yielded positive results in terms of improved hemoglobin levels and loss of transfusion dependence, with hardly any side effects. A phase 3 trial to compare luspatercept to ESAs (COMMANDS study) is ongoing.Luspatercept is a promising alternative to ESAs for a subset of transfusion-dependent patients with lower risk MDS, namely those with a sideroblastic phenotype who are either not suitable for or have already failed erythropoietin-based treatment. The favorable safety profile and convenient subcutaneous administration every 3 weeks are more conducive to patients' quality of life than chronic red blood cell transfusion therapy.

ZusammenfassungDie vorliegende Arbeit soll einen Überblick über Diagnostik und Therapie der myelodysplastischen Syndrome (MDS) darstellen, aber auch aktuelle wissenschaftliche Fragestellungen zur Ätiopathogenese, Pathophysiologie und Klassifikation der myeloischen Neoplasien erläutern, die den Blickwinkel auf die MDS in mancher Hinsicht erweitern können und möglicherweise in Zukunft auch in der Klinik Berücksichtigung finden werden.

The European Leukemia Net (ELN) guidelines for treatment of myelodysplastic syndromes (MDS) connect heterogeneous MDS subgroups with a number of therapeutic options ranging from best supportive care to allogeneic stem cell transplantation (alloSCT). However, it is currently unknown whether adherence to guideline recommendations translates into improved survival. The sizeable database of the Duesseldorf MDS Registry allowed us to address this question. We first performed a retrospective analysis including 1698 patients (cohort 1) to whom we retrospectively applied the ELN guidelines. We compared patients treated according to the guidelines with patients who deviated from it, either because they received a certain treatment though it was not recommended or because they did not receive that treatment despite being eligible. We also performed a prospective study with 381 patients (cohort 2) who were seen in our department and received guideline-based expert advice. Again, we compared the impact of subsequent guideline-adherent versus non-adherent treatment. For the majority of treatment options (best supportive care, lenalidomide, hypomethylating agents, low-dose chemotherapy, and intensive chemotherapy), we found that adherence to the ELN guidelines did not improve survival in cohort 1. The same was true when patient management was prospectively enhanced through guideline-based treatment advice given by MDS experts (cohort 2). The only exceptions were alloSCT and iron chelation (ICT). Patients receiving ICT and alloSCT as recommended fared significantly better than those who were eligible but received other treatment. Our analysis underscores the limited survival impact of most MDS therapies and suggests to pursue alloSCT in all suitable candidates. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00277-020-04325-7.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with advanced myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (sAML), but in the absence of prospective trials the impact of pretransplant cytoreduction is controversially discussed. We retrospectively analyzed the outcome of 165 patients with MDS and excess blasts (n = 126, 76%) and sAML (n = 39, 24%) according to a pretransplant strategy. Sixty-seven patients (41%) were directly transplanted (upfront group), whereas 98 patients (59%) had received pretransplant cytoreductive treatment (induction chemotherapy [CTX], n = 64; hypomethylating agents [HMAs], n = 34) resulting in a significantly higher complete remission rate in the CTX group (59% versus HMA 18%, P.0001). Estimated rates of 5-year overall survival (OS) and relapse-free survival (RFS) for the entire group were 54% and 39%, respectively. The 5-year OS rates of the upfront, CTX, and HMA groups were 61%, 50%, and 45%, respectively (P = .116), whereas RFS rates were 38%, 41%, and 38% (P = .926). Cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) did not differ between treatment groups. In the upfront group no difference regarding OS and RFS was seen with respect to pretransplant blast count (10% versus10%). In multivariate analyses type of pretransplant strategy did not have an effect on OS, RFS, CIR, and NRM, whereas cytogenetics (OS, RFS, CIR), reduced-intensity conditioning (OS, RFS, CIR), and an unrelated donor (RFS, CIR) were identified as negative predictors. When compared with the upfront group, 5-year OS was significantly lower in patients with CTX-refractory disease (34% versus 64%, P = .0346) and by clear trend in HMA nonresponders (42% versus 61%, P = .073), whereas RFS did not differ significantly. In further support of the concept, that pretransplant therapy may favor the selection of resistant clones, patients in the upfront group had a higher likelihood to respond to HMAs as salvage therapy for relapse in comparison with pretreated patients (complete remission, 58% versus 10%; P = .0005) and a higher 2-year OS rate after relapse (59% versus 19%, P = .0001). These data suggest that an upfront transplant strategy is at least not inferior to pretransplant cytoreduction and may be augmented by HMAs + donor lymphocyte infusion salvage therapy in case of relapse after allo-HSCT.

Allogeneic hematopoietic stem cell transplantation (aHSCT) cures a considerable number of patients with myeloid malignancies, but relapse is the most frequent cause of death. We retrospectively studied relapse rate, kinetics, treatment, and outcome after first aHSCT in 446 patients during a 13-year period. Relapse occurred in 167 patients after a median of 4.6 months (116 hematologic (HR), 38 molecular (MR), and 13 extramedullary relapses (XR)). Median survival after relapse was 8.4 months and 2-year overall survival was 25%. Regarding survival after relapse, type (MR/HR/XR) and timepoint of relapse (/ 12 months), age (/ 50), diagnosis (MDS/AML and sAML), and remission status at transplant (CR and untreated MDS vs. refractory disease) were relevant in univariate analyses, in multivariate analyses timepoint, and type of relapse, age, and diagnosis. One hundred fifty-six patients were treated, most frequently with hypomethylating agents (HMA, n = 109) or intensive chemotherapy (n = 12). Donor lymphocyte infusion (DLI) was administered to 99 patients. Second aHSCT was performed in three patients as first and in 21 as higher salvage treatment. A complete remission (CR) was achieved in 46 patients (30%). Among CR patients, 65% had received HMA and DLI. Median survival of patients achieving CR was 105 months and 2-year overall survival was 80%. We conclude that with HMA and DLI or second aHSCT, a substantial number of patients, who relapse after aHSCT, can re-achieve remission and long-term survival. Techniques to further improve the detection of minimal residual disease are urgently needed because early treatment of MR results in significantly better survival.

Participation in clinical trials may allow patients with MDS to gain access to therapies not otherwise available. However, access is limited by strict inclusion and exclusion criteria, reflecting academic or regulatory questions addressed by the respective studies. We performed a simulation in order to estimate the average proportion of MDS patients eligible for participation in a clinical trial. The simulation drew upon 1809 patients in the Dusseldorf MDS Registry whose clinical data allowed eligibility screening for a wide range of clinical trials. This cohort was assumed to be alive and available for study participation. The simulation also posited that all MDS trials (n = 47) conducted in our center between 1987 and 2016 were open for recruitment. In addition, study activities in the year 2016 were analyzed to determine the proportion of patients eligible for at least one of the 9 MDS trials open at that time. On average, each clinical trial was suitable for about 18 % of patients in the simulation cohort. Conversely, 34 % of the patients were eligible for at least one of the 9 clinical studies in 2016. Inclusion/exclusion criteria of studies initiated by the pharmaceutical industry excluded more than twice the fraction of patients compared with investigator initiated trials (potential inclusion of 10 % vs. 21 %, respectively). Karyotype (average exclusion rate 58 %), comorbidities (40 %), and prior therapies (55 %) were the main reasons for exclusion. We suggest that in- and exclusion criteria should be less restrictive, in order to meet the needs of the real-life population of elderly MDS patients.

Introduction: Iron storage in patients (pts) with myelodysplastic syndromes at the time of diagnosis may vary from normal to iron overload. Even before the first blood transfusion, storage iron can be increased due to down-regulation of hepcidin and subsequent increase in duodenal iron uptake. Iron overload is known to worsen the prognosis of MDS patients, partly due to iron-related organ damage after long-term transfusion therapy, and partly due to an increased risk of infections. However, it is unclear whether increased storage iron at the time of diagnosis already has a prognostic influence. We assessed bone marrow iron stores at the time of MDS diagnosis and correlated them with clinical outcome. Methods: In a retrospective analysis of 3762 adult MDS patients from the Düsseldorf MDS Registry, Prussian blue staining of marrow smears was performed in our cytology lab to assess iron stores according to the following categories: normal or decreased iron stores versus increased iron stores versus iron overload. Patients were followed up for survival and AML evolution until June 2021. Median time of follow-up was 20 months. 67.4% of the patients died during the course of the disease. Results: The study included 3.762 adult patients who received their initial diagnosis of MDS between 1970 and 2021. 58% were diagnosed as non-blastic MDS ( MDS SLD (RS) (n=240), MDS MLD (RS) (n=350), MDSdel(5q) (n=107), and MDS-U (n=25). Iron stores were decreased in 8% of the patients, normal in 44%, increased in 41%, and strongly increased in 7% (massive iron overload). In 282 cases, histologic assessment of storage iron was available. When comparing cytologic and histologic assessment, we found a strong correlation (p The cumulative risk of AML evolution was not associated with the results of iron staining. Regarding survival, we found that patients with decreased or normal storage iron had a median survival of 31 months, whereas those with increased iron had a median survival of 28 months (p=0.007). Focusing on patients with non-blastic MDS, the difference was not significant (46 vs 44 ms). However, patients who presented as EB I (n=435), EBII (n=510), AML MRC (n=264), CMML I (n=254), or CMML II (n=77), showed a prognostic impact of storage iron; patients with increased iron had a median survival of 11 months, as compared to 16 months in patients with normal or decreased iron (p Conclusion: Increased tissue iron in the bone marrow at the time of diagnosis is associated with inferior survival in patients with MDS, primarily in patients with higher risk MDS. At diagnosis, patients are not yet transfusion-dependent. This suggests that increased iron reflects a prolonged period of increased duodenal iron uptake as a consequence of ineffective erythropoiesis. Therefore, increased marrow iron at the time of MDS diagnosis seems to be a surrogate parameter of hematopoietic insufficiency, which is the real cause of inferior prognosis. Disclosures Nachtkamp: Jazz: Honoraria; Bsh medical: Honoraria; Celgene: Other: Travel Support. Gattermann: Novartis: Honoraria; Takeda: Research Funding; Celgene: Honoraria. Germing: Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding.

Introduction Rituximab (R) administration results in significant outcome improvement in B cell precursor acute lymphoblastic leukemia (B-ALL) patients (pts), but is usually restricted to pts with ≥20% CD20+ leukemic blasts. Yet, this arbitrary cut-off is not proven biologically sensible. Moreover, CD20 expression might differ between blood (pb) and bone marrow (bm) and varies under prednisone during early treatment. In the present GMALL08/2013 trial R is administered to all BCR-ABL1-negative B-ALL pts irrespective of the initial leukemic CD20 expression. We assessed the initial and post-prephase CD20 expression in GMALL08/2013 pts and correlated the values with MRD response after Induction I (Ind I) and Consolidation I (Cons I). A historical B-ALL GMALL07/2003 cohort without R treatment and with available CD20 expression and MRD data was used to evaluate for R-unrelated effects. Methods Comparative immunophenotypic quantification of CD20 expression in 207 B-ALL pts was performed at diagnosis (pb d0 and/or bm d0) and/or (a/o) after a 5-day dexamethasone- and cyclophosphamide-containing prephase (pb d6) under EuroFlow standardized procedures. CD20 median fluorescence intensities (CD20-MFI) and percentages of CD20+ B-ALL blasts/all blasts (%CD20+ BL) were assessed. Minimal residual disease (MRD) was determined after Ind I (after 1x R) and Cons I (after 4x R) by quantitative PCR for clone-specific immune gene rearrangements to stratify pts as molecular complete response (MolCR, MRD negativity, assay sensitivity at least 1x10 -4), molecular intermediate response (MolIR, MRD positive non-quantifiable or positive Results bm d0/pb d0. In 91 paired bm d0/pb d0 samples %CD20+ BL as well as the CD20-MFI were significantly higher in pb in common/pre-B ALL (c/pre-B ALL) (n=76: paired t-test: p pb d0/pb d6. CD20 expression of circulating blasts significantly increased after a 5-day prephase in c/pre-B ALL but not in pro-B ALL in 106 paired pb d0/pb d6 samples (paired t-test of CD20-MFI and %CD20+ BL; n=20 pro-B ALL, p=.09 and p=.25; n=86 c/pre-B ALL, p Molecular response under R. The values of %CD20+ BL were correlated with MRD response after Ind I and Cons I (Fig. 3). Since the CD20 expression in the present cohort was shown to be significantly modulated in a drug- and compartment-dependent manner, we used the highest measured value of %CD20+ BL out of the three available values per patient (bm d0, pb d0 a/o pb d6). In the historical cohort (n=145) one value per patient for %CD20+ BL was available. Due to low CD20 expression pro-B ALL did not show any differences in the %CD20+ BL among the risk groups in the present (Ind I n=23, Cons I n=20) and the historical (Ind I n=11; Cons I n=11) cohort. The differences in %CD20+ BL in relation to molecular response were significant in c/pre-B ALL between MolCR and MolFAIL after Ind I (n=127) and Cons I (n=120) (Mann-Whitney test: p=.0002 and p=.0028) and of lower significance between MolIR and MolFAIL after Ind I (p=.013) and between MolCR and MolIR after Cons I (p=.029) in the present cohort. Within the historical cohort (Ind I n=145, Cons I n=143) no significant differences were observed. Conclusions Leukemic CD20 expression was modulated between compartments (bm d0/pb d0) and showed a significant increase in a drug-dependent manner in c/pre-B ALL (pb d0/pb d6) probably in response to dexamethasone. The results might challenge the conventional eligibility criteria for CD20 targeted treatment in c/pre-B ALL. MRD persisters showed lower initial CD20 expression compared to MRD responders in the present cohort consistently receiving R, but not in the historical cohort without R treatment. Accordingly, R seems to improve the early MRD response predominantly in pts with higher CD20 expression. Supported by DJCLS Figure 1 Figure 1. Disclosures Szczepanowski: Amgen: Speakers Bureau. Trautmann: Amgen: Speakers Bureau. Ritgen: Roche: Consultancy, Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support, Research Funding; Chugai: Consultancy; MSD: Consultancy, Other: Travel support; Celgene: Other: Travel support. Nachtkamp: Celgene: Other: Travel Support; bsh medical: Speakers Bureau; Jazz: Speakers Bureau. Viardot: Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment. Baldus: Jazz: Honoraria; Celgene/BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Schwartz: Morphosys: Research Funding; Gilead: Other: Travel grants, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Basilea: Other: Travel grants. Goekbuget: Pfizer: Consultancy, Other: Research funding for institution; Amgen: Consultancy, Other: Invited talks for company sponsored symposia (with honoraria); Research funding for institution; Astra Zeneca: Other: Invited talk for company sponsored symposia (with honor); Gilead/Kite: Consultancy; Novartis: Consultancy, Other: Research funding for Institution; Jazz Pharmaceuticals: Other: Research funding for institution; Incyte: Other: Research funding for Institution; Cellestia: Consultancy; Erytech: Consultancy; Morphosys: Consultancy; Servier: Consultancy, Other; Abbvie: Other. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. OffLabel Disclosure: Rituximab administration to patients with CD20-negative (

Introduction: Infections are a well-recognized complication in patients (pts) with myelodysplastic syndromes (MDS) that contribute substantially to the morbidity and mortality particularly in pts suffering from neutropenia. Neutropenia and other immune defects including impaired neutrophil function have been reported to be predisposing factors for severe infections. Furthermore, some of the therapies may worsen neutropenia and lead to an additional risk factor to develop infectious episodes. Since infectious complications are no primary endpoint in clinical trials epidemiological data on infections in large cohorts of MDS pts is sparse. Methods: We performed a retrospective analysis of 3.787 MDS-patients from the Duesseldorf MDS Registry who were diagnosed between 1980 and 2018. Infectious complications were defined as clinical symptoms of infection associated with the need for antibiotic and/or antifungal therapy, and/or the isolation of a pathogen and/or an identifiable site of infection by physical examination. Infectious episodes were categorized as fever of unknown origin, microbiologically or clinically documented infection. Results: Amongst our study cohort, 42% of the pts suffered from at least one infectious complication of any type during the course of their disease. Most infectious diseases were of bacterial origin (34.7%) and in 17% a pathogen was isolated. Pneumonia was the most common site of infection (64%). Pts who experienced at least one infectious episode had a significant poorer overall survival (OS) than pts without such events (21 vs 37 months, p In univariate analyses comparing pts who had no infections versus those who had one or more, pts with older age (>65 years) tended to have a higher incidence of infectious episodes (p We found a highly significant negative correlation between the depth of cytopenia in all three myeloid lineages and the presence of infections (p Conclusion: The incidence of infections significantly increases in pts with advanced age. MDS-pts in general are more vulnerable for infection-related morbidity and mortality than non-MDS-pts. Low hemoglobin and platelet counts were both found to be associated with a worse prognosis compared to low neutrophil counts. The appearance of at least one infectious episode leads to an inferior Disclosures Nachtkamp: Jazz: Speakers Bureau; bsh medical: Speakers Bureau; Celgene: Other: Travel Support. Kobbe: Celgene: Research Funding. Gattermann: Celgene: Honoraria; Takeda: Research Funding; Novartis: Honoraria. Germing: Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria.

In the past decade outcome of adult ALL was improved significantly using pediatric-based chemotherapy in combination with risk-adapted stem cell transplantation (SCT) and targeted therapies. The GMALL Trial 08/2013 (NCT02881086) for patients (pts) aged 18-55 years (yrs) with newly diagnosed ALL/LBL has a BFM-based 2-phase induction, up to 8 cycles of PEG-asparaginase (ASP) with up to 7 cycles of HDMTX, HDAC, a reinduction phase and conventional maintenance up to 2.5 yrs. Two cycles Nelarabine are implemented for standard risk (SR) T-ALL. Pts with B-precursor-ALL (B-ALL) receive Rituximab independent of CD20 expression (Ph+ only if CD20+). Ph+ ALL pts receive Imatinib and a dose reduced induction (Vincristine, Dexamethasone, ASP). ASP is scheduled in induction 1 (IP1) (d 20) and 2 (d 34 for Ph+ and d 44 for Ph-) and dose is adapted to risk factors for hepatotoxicity. Pts with BMI>30 and/or liver steatosis receive 500 U/m 2, whereas 2000 U/m 2 is the standard dose. It is recommended to withhold the 2 nd dose of ASP in case of clinically relevant ASP-associated toxicities. Pts with high-risk (HR) features (WBC > 30,000/µl in B-ALL, pro B-ALL-, KMT2A rearrangement, early/mature T-ALL) or Ph+ ALL are considered for SCT in CR1 after 1 st consolidation (C1). Pts with MolFail (table 1) after C1 are candidates for targeted therapy (Blinatumomab, Nelarabin) followed by SCT. Randomization (R) I evaluates CNS irradiation versus i.th. prophylaxis in B- ALL/LBL. R II compares SCT versus SR therapy in HR pts with MolCR after induction. Both randomizations are blinded and not available for analysis. The trial is ongoing and scheduled to recruit 950 pts. Between 8/2017-4/2021 770 pts from 78 centers were included and 705 were evaluable. The median age was 35 (18-55) yrs, 638 had ALL (B,Ph-: 55%, Ph+: 20%, T: 25%,) and 67 pts LBL (B:12%; T:88%). For ALL the hematologic (Hem) CR rate after C1 was 93% and the MolCR Rate 61% (75% mol. response) (table 1). HemCR rate was 72% in LBL with 21% PR. PET CT was negative in half of the LBL PR cases. The lowest HemCR rate was observed in early T-ALL (83%) together with a MolCR rate of 45% (71% mol. response). In Ph- pts 2000 U/m 2 as first dose ASP was administered in 66%, 500 U/m 2 in 24%, no ASP in 1% and other doses in 9%. In pts with Ph+ ALL the respective numbers were 61%, 21%, 6% and 13%. For the 2nd dose the numbers were 43%, 21%,13% and 22% for Ph- and 41%, 24%, 13% and 22% for Ph+ pts. Bilirubine increases grade III/IV were observed in Ph- ALL in 18% of the cases treated with 500 U/m 2 vs 24% for 2000 U/m 2. In Ph+ ALL the respective numbers were 5% vs 3%. GOT/GPT grade III/IV increases were observed 29% of Ph- ALL pts treated with 500 U/m 2 vs 25% of those with 2000 U/m 2. The respective numbers for Ph+ ALL were 24% and 40%. At a median follow-up of 23 mo, the overall survival (OS) for all pts (N=705) was 88% and 76% at 1 and 3 yrs resp (subgroups see table 1). OS was correlated to age, 87%, 74%, 69% and 73% at 3 yrs for pts aged 18-25, 26-35, 36-45 and 46-55 yrs resp. SR T-ALL reached an OS of 86% at 3 yrs with a conventional and nelarabine based consolidation. 79% of pts with an indication for SCT were transplanted (64 sibling, 174 MUD). The OS of SCT pts after SCT was 75% at 3 yrs. 63 pts with MolFail became candidates for a targeted therapy, which was realized in 89% of the cases. The molecular response was evaluable in 51 pts and reached 55% (N=40) and 18% (N=11) after one cycle of Blinatumomab or Nelarabin resp. Pts with MolFail (N=63) achieved an OS of 84% at 1y and 72% at 3 years resp (71% for Ph- and 76% for Ph+). This large, ongoing prospective multicenter trial provides promising preliminary results. This applies also to those aged 45-55 yrs underlining that adult pts beyond the variable AYA definitions can benefit from pediatric-based therapy. Intensive and individualized ASP therapy was feasible. Whereas high HemCR rates were observed in nearly all subgroups, MolCR rates ranged from 41-74% and a relevant proportion remained MRD low positive underlining the need for detailed MRD classification. MRD-based targeted treatment was realized in a high proportion of pts. Responses to Blinatumomab in MolFail were lower compared to previous trials. Responses to Nelarabine in MolFail T-ALL pts were only 18%. OS of MolFail pts however was promising with the combination of targeted therapy and SCT. Thus, SCT is still a key component, contributing to improved outcomes although the overall proportion of SCT was lower than in previous GMALL trials. Funded by Deutsche Krebshilfe Figure 1 Figure 1. Disclosures Goekbuget: Servier: Consultancy, Other; Morphosys: Consultancy; Astra Zeneca: Other: Invited talk for company sponsored symposia (with honor); Amgen: Consultancy, Other: Invited talks for company sponsored symposia (with honoraria); Research funding for institution; Novartis: Consultancy, Other: Research funding for Institution; Pfizer: Consultancy, Other: Research funding for institution; Jazz Pharmaceuticals: Other: Research funding for institution; Incyte: Other: Research funding for Institution; Cellestia: Consultancy; Erytech: Consultancy; Abbvie: Other; Gilead/Kite: Consultancy. Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Viardot: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nachtkamp: Jazz: Honoraria; Bsh medical: Honoraria; Celgene: Other: Travel Support. Topp: Novartis: Consultancy; Roche: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy, Research Funding; Macrogeniecs: Research Funding; Regeneron: Consultancy, Research Funding; Gilead: Research Funding; Universitatklinikum Wurzburg: Current Employment. Wäsch: Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Vucinic: Abbvie: Honoraria, Other: Travel Sponsoring; MSD: Honoraria; Janssen: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Pfeifer: Incyte: Honoraria, Research Funding. Schwartz: Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Basilea: Other: Travel grants; Gilead: Other: Travel grants, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Morphosys: Research Funding. Fiedler: Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding; Ariad/Incyte: Honoraria; Celgene: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; MorphoSys: Consultancy, Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material; Stemline: Consultancy; Servier: Consultancy, Other: Meeting attendance, Preparation of information material. OffLabel Disclosure: Nelarabine in newly diagnosed T-ALL

Introduction: Acute lymphoblastic leukemia (ALL) represents approx. 5% of all newly diagnosed leukemias in patients between 55 and 70 years of age. Despite recent advances especially in younger patients, the prognosis of elderly patients with ALL remains dismal, even after moderately intensive chemotherapy. Incorporation of antibody-based therapies in the first line induction therapy bears the potential of a significant increased response rate and survival with the reduction of treatment toxicity. Methods: This open label phase II study of the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia was conducted at 13 centers. Patients aged >55 years with newly diagnosed Ph/BCR-ABL negative acute B-precursor ALL were eligible. Leukemic blasts had CD22 surface expression of at least 20%. The 1st induction cycle consisted of InO 0.8mg/m2 on day1 and 0.5mg/m2 on d8 and d15 together with dexamethasone 10 mg/m2 (day7-8, day14-17) and one intrathecal injection (i.th.) of methotrexate (MTX), cytarabine (AraC) and dexamethasone (Dex). The 2nd and 3rd induction cycle consisted of InO 0.5mg/m2 on day 1, 8 and 15 plus i.th. MTX/AraC/Dex. Patients achieving a complete remission (CR) were offered to receive 5 conventional consolidation therapies (3 x ID-MTX/asparaginase; 2 x ID-AraC) and one reinduction therapy (idarubicine/ AraC/ cyclophosphamide / Dex.) in combination with rituximab (for CD20+ ALL), followed by a maintenance therapy with 6-MP/MTX. The primary endpoint was event free survival (EFS) at 12-months follow-up. An event was defined as any of the following: persisting bone marrow blasts after 2 cycles of InO, relapse or death. An event rate of ≤40% at 12 months follow-up was considered to qualify the experimental treatment as very promising for additional testing. Under the assumption of one-sided type I error of 5% and 80% power, 42 evaluable patients were needed for primary endpoint analysis (registered with ClinicalTrials.gov, identifier: NCT03460522). Results: As of July 2021, 45 patients were included, with induction results available for 43 patients. Two patients were excluded per protocol from further analysis, as they received only one induction: 1 prolonged toxicity (CR after induction), 1 withdrawn consent. Median age at initial diagnosis was 64 years (range 56-80 years). 38 patients were diagnosed with a common- and 5 with a pro-B ALL. Median CD22 expression on leukemic blasts was 69% (range 21-99%). Due to suspected therapy related liver toxicities, a single patient received only 2 induction cycles (complete remission after 1st induction). All other patients completed 3 cycles of induction therapy and achieved complete remission (CR/CRi), mainly after the 1st induction. Results of minimal residual disease (MRD), measured by real-time quantitative PCR, are available for all 43 patients, with 23/43 (53%) and 31/42 (74%) patients being MRD negative after 2nd and 3rd induction therapy, respectively. Four patients with MRD failure (≥10 -4) after the 3rd induction therapy are still in CR (2 were treated with conventional chemotherapy per this protocol, one proceeded to allogeneic stem cell transplantation (aSCT), one received blinatumomab). MRD below the threshold of 10 -4 was detected in 15 patients after the 2nd induction (no relapse occurred so far). 8 of these 15 patients were MRD negative after the 3rd induction. So far, 7 events have been reported (during year 1: 3 deaths in CR and 1 relapsed ALL; during year 2: 1 death in CR and 2 patients with relapse). With a median follow-up of 422 days, the probability of OS at 1 and 2 years is 91% (95% C.I. 80-100%) and 77% (95% C.I. 57-96%), respectively. 4 patients received an aSCT in 1st CR, 1 patient in 2nd CR. Regarding adverse events (AEs) during induction cycles 1, 2 and 3, most common AEs ≥CTC grade 3 reported were leukocytopenia (in 60%, 12% and 3% of all cases, respectively), anemia (28%, 2%, 0%), thrombocytopenia (35%, 7%, 3%) and elevation of liver enzymes (14%, 5%, 0%). So far, one patient has been reported with suspected veno occlusive disease (after 2nd induction therapy). Conclusion: Three cycles of InO as induction therapy for the treatment of elderly patients with acute B-cell ALL results in very high remission rates with MRD-response in up to 90% (MRD negativity or MRD-levels Figure 1 Figure 1. Disclosures Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; MSD: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Wäsch: Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Nachtkamp: Jazz: Honoraria; Bsh medical: Honoraria; Celgene: Other: Travel Support. Haenel: Jazz: Consultancy, Honoraria; GSK: Consultancy; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget: Amgen: Consultancy, Other: Invited talks for company sponsored symposia (with honoraria); Research funding for institution; Astra Zeneca: Other: Invited talk for company sponsored symposia (with honor); Erytech: Consultancy; Cellestia: Consultancy; Incyte: Other: Research funding for Institution; Jazz Pharmaceuticals: Other: Research funding for institution; Novartis: Consultancy, Other: Research funding for Institution; Gilead/Kite: Consultancy; Morphosys: Consultancy; Pfizer: Consultancy, Other: Research funding for institution; Servier: Consultancy, Other; Abbvie: Other. OffLabel Disclosure: Inotuzumab Ozogamicin

In contrast to the evidence regarding azacitidine (Aza), there is limited knowledge about the combination of decitabine (DAC) and donor lymphocyte infusions as salvage therapy for relapse after allogeneic stem cell transplantation (allo-SCT) so far. We retrospectively analyzed data of 36 patients with hematological (n = 35) or molecular relapse (n = 1) of acute myeloid leukemia (AML, n = 29) or myelodysplastic syndrome (MDS, n = 7) collected from 6 German transplant centers. Patients were treated with a median of 2 cycles DAC (range, 1 to 11). DAC was the first salvage therapy in 16 patients (44%), whereas 20 patients (56%) had previously received 1 to 5 lines of salvage therapy including 16 of them had been treated with Aza. In 22 patients (61%), a median of 2 DLI per patient (range, 1 to 5) was administered in addition to DAC. As a result, overall response rate was 25% including 6 complete remissions (CR, 17%) and 3 partial remissions (PR, 8%). Three patients within the first-line group achieved CR, while also 3 patients receiving DAC as second-line treatment reached CR including 2 patients with previous Aza failure. Median duration of CR was 10 months (range, 2 to 33) and no patient relapsed so far. The 2-year OS rate was 11% (± 6%) without any difference between first-line and pretreated patients. Incidence of acute and chronic graft-versus-host disease was 19 and 5%. Taken together, DAC exerts clinical efficacy in patients with AML or MDS relapsing after allo-SCT and is able to induce durable remissions in individual patients suggesting that DAC may be an alternative to Aza or even a second choice after Aza failure.

The heterogeneous group of myelodysplastic syndromes (MDS) needs an individualized and patient-tailored therapeutic approach. Consensus-based guidelines for diagnosis and treatment provide a basis for clinical decision making. MDS guidelines are issued by expert panels. Our main objective was to examine how guidelines influence patients’ adherence to expert recommendations and how they ensure healthcare quality. To approach this question, we reviewed the most common guidelines for diagnosing and treating MDS in adult patients. Furthermore, we critically looked at quality indicators for everyday practice and studied adherence in an everyday outpatient setting. Finally, we also paid close attention to patient-reported outcome measures and studied how they are used as endpoints in clinical trials. We can conclude that the combination of evidence-based diagnostic tools, standardized treatment recommendations, and patient-centered shared decision making will eventually lead to a healthcare standard that will significantly improve outcomes in adult patients with MDS.

Introduction The effect of adherence to treatment guidelines has not yet been evaluated in myelodysplastic syndromes (MDS). Based on the large Düsseldorf MDS Registry, we explored adherence to European LeukemiaNet (ELN) guidelines as well as MDS expert recommendations in clinical routine. Methods In a preliminary retrospective analysis of 1658 patients documented in the Düsseldorf MDS registry, we reviewed if treatment was in accordance with the published ELN guidelines from 2014. The following treatments were considered: erythropoiesis stimulating agents (ESA), iron chelation, Lenalidomide, hypomethylating agents (HMA), intensive chemotherapy, and allogeneic stem cell transplantation (alloSCT). Since patients were diagnosed between 1982 and 2018, clinical decision-making could not be exclusively based on current guidelines. Therefore, we also performed a prospective analysis of 381 patients who received patient-tailored treatment recommendations, considering, IPSS-R, MDS-CI, HCT-CI, distance to our center, and ELN guidelines, with special attention to the above-mentioned treatment options. In addition, we conducted a matched-pair analysis, comparing patients who received a certain treatment with patients who, though eligible, did not receive it. Information regarding adherence to treatment recommendations was obtained by searching medical files and contacting primary care physicians. Probability of survival was estimated using the Kaplan-Meier method. Results The retrospective cohort was followed for a median of 22 months (1-500 months). Patients treated in accordance with the ELN guideline did not gain a significant survival benefit in the subgroups treated with ESA, iron chelation, Lenalidomide, HMA, and intensive chemotherapy, compared to patients who were eligible for the respective treatment but did not receive it. Solely the group of patients undergoing alloSCT derived a significant survival benefit compared to patients not receiving alloSCT despite qualifying for this treatment according to ELN criteria (30 vs 18 months, p=0.011, 95% CI 16.86; 25.14, fig. 1). The prospective cohort was followed for a median of 14 months (1-195 months). A median of four months elapsed before treatment was started. Non-adherence to patient-tailored therapeutic recommendations was found in 33% of the patients. The proportion of non-adherence was higher for intensive chemotherapy (47%) and lowest for patients receiving supportive treatment (13%) like ESA and chelation therapy. In the prospective group, the matched-pair study showed again that patients receiving ESA, iron chelation, Lenalidomide, HMA or intensive chemotherapy did not gain a significant survival benefit from adherence to the respective treatment recommendations. Again, survival only differed between patients adhering to and patients not adhering to a recommendation for alloSCT (median survival of 74 vs 28 months; 95% CI 7.5; 48.5, p=0.015). Conclusions According to current ELN guidelines, 33% of patients did not receive the treatment they were eligible for. Non-adherence to patient-tailored treatment recommendations from our tertiary referral center was found in 33% of the patients. Based on our two patient cohorts, supportive care regimens, Lenalidomide, HMA, as well as intensive chemotherapy do not appear to improve overall survival, whereas allogeneic stem cell transplantation provided a significant survival benefit in both groups. In summary, while adherence to MDS treatment guidelines and expert recommendations may influence survival in some of the patients, the overall effect appears to be limited, owing to the limited efficacy of the available treatment options, with the notable exception of alloSCT. However, we cannot exclude that adherence to treatment recommendations has an effect on other relevant outcomes such as quality of life or frequency of hospitalisations due to infections, bleeding and cardiovascular events. Finally, a systematic and standardized assessment of guideline-adherence, reasons for non-adherence, and impact on relevant outcomes would be desirable because it would support us in monitoring the quality of care of MDS patients and would allow comparisons to be made between different health economic environments. Disclosures Nachtkamp: Jazz Pharmaceuticals: Honoraria; Celgene: Other: Travel Support. Schroeder:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kobbe:Amgen: Honoraria, Other: Travel support, Research Funding; Neovii: Honoraria, Other: Travel support; Abbvie: Honoraria, Other: Travel support; Roche: Honoraria, Other: Travel support; Biotest: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support, Research Funding; Pfizer: Honoraria, Other: Travel support; Jazz: Honoraria, Other: Travel support; Takeda: Honoraria, Other: Travel support; Medac: Honoraria, Other: Travel support; MSD: Honoraria, Other: Travel support; Novartis: Honoraria, Other: Travel support. Kündgen:Otsuka: Honoraria; Takeda: Honoraria, Other: Travel Support; Novartis: Honoraria. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Rautenberg:Jazz Pharmaceuticals: Other: Travel Support; Celgene: Honoraria, Other: Travel Support. Gattermann:Novartis: Honoraria; Alexion: Research Funding; Takeda: Research Funding. Bonadies:Novartis: Other: financial support for travel, Research Funding; Roche: Other: financial support for travel, Research Funding; Amgen: Other: financial support for travel; Celgene: Other: financial support for travel, Research Funding; Sanofi Genzyme: Other: financial support for travel; Janssen: Other: financial support for travel. Germing:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria.

Background During the last years Azacitidine (Aza) in combination with donor lymphocyte infusions (DLI), has proven to be a valuable treatment option for pts with relapse of MDS or AML after allo-SCT. Reasoning that Lenalidomide (Len) may further improve response rate and outcome due to its immunomodulatory and antileukemic properties, we initiated a prospective, multicenter, single-arm phase-II trial evaluating the combination of Aza, Len and DLI in patients with MDS, AML or CMML who had relapsed after allo-SCT. To acknowledge the risk of triggering GvHD with Len this study comprises two safety interim analyses. Results from the interim analysis I on the first 10 pts did not reveal a dose limiting toxicity (DLT) enabling an increase in the daily Len dosage from 2.5 mg to 5 mg in next cohort. Design/Methods: This planned second interim safety analysis (data lock March 2018) was performed in the next 10 pts who were treated with a daily dose of 5 mg Len for 21 days of a 28-day cycle in combination with up to 8 cycles Aza (75 mg/m2/d d1-7, every 28 days) and 3 DLI with increasing T cell dosages (0.5×106 - 1.5×107 cells/kg). In addition, we here present efficacy and safety results of all 24 pts included in this trial so far. The protocol demands a dose reduction of Len to 2.5 mg/day for the remaining 30 patients in case of DLT defined as steroid refractory aGvHD grade III/IV, cGvHD NHI score severe or any unexpected hematologic and non-hematological toxicity grade ≥III in more than 3 pts. In the absence of DLT in more than 3 pts the study will be continued with 5 mg/day. Results: Overall, 24 pts, who had suffered from molecular (54%) or hematological (46%) relapse of MDS (58%), AML (38%) or CMML (4%) after median of 260 days (range, 61-2659) following allo-SCT, were treated with a median of 5.5 cycles of Len per patient (range, 1 to 8; total no. of cycles 121; 83 cycles 2.5 mg/day, 38 cycles 5 mg/day). Concomitantly, pts received a median of 7 courses Aza (range 2-8) and 17 pts (71%) received at least one DLI (median: 2, range: 1-12). No DLT was seen in the cohort of 10 pts treated with a Len dosage of 5mg/day. Furthermore, the increased Len dose did neither result in a higher frequency of dose reductions and treatment interruptions in this cohort, nor to a higher number of AE per cycle (2.5 mg/day: 5.45 AE vs. 5 mg/day: 3.15 AE). We observed an overall response rate of 68% (CR 58%, PR 10%). CR rate was by trend higher in pts with molecular than in those with hematological relapse (67% vs. 43%) and all pts with CR remained in remission for a median of 183 days (range, 113-513) so far. Four pts (17%) developed acute GvHD (overall grade II, II, III, III) and 5 pts (21%) chronic GvHD (mild n=2; moderate n=2; severe n=1). While therapy-related CTC grade III/IV neutropenia (90%), thrombopenia (71%) or anemia (29%) occurred frequently, non-hematological adverse events (AE) >grade II were rare and mainly consisted of gastrointestinal toxicity, laboratory findings and infections. Conclusion: This 2nd interim-analysis of the AZALena-trial shows, that an increase in the Len dosage to 5 mg/day is feasible, safe and not associated with excess GvHD and toxicity. Consequently, 5 mg/day Len will be used in the remaining pts who will be included in this trial (total no. of pts planned, n=50). Furthermore, results from all 24 pts suggest that the combination of Aza, Len and DLI has promising clinical activity and can induce durable responses in a substantial proportion of pts with MDS and AML who relapse after allo-SCT. Disclosures Schroeder: Celgene: Consultancy, Honoraria, Research Funding. Rautenberg:Celgene: Honoraria. Stelljes:MSD: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Scheid:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria. Beelen:Medac: Consultancy, Other: Travel Support. Germing:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kobbe:Celgene: Honoraria, Other: Travel Support, Research Funding; Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

During the last years, more and more treatment modalities are available for MDS patients. Therefore, we were interested if this is reflected in an improvement of the outcome of the patients. We analyzed the survival and rate of leukemic progression of 4147 patients from the Duesseldorf MDS registry diagnosed during the last 30 years and found an improvement of survival in those patients diagnosed after 2002 (30 vs. 23 months, p0.0001). In detail, the improvement of the prognosis was restricted to high-risk MDS patients diagnosed between 2002 and 2014 in comparison to the patient group diagnosed between 1982 and 2001 (19 vs. 13 months, p0.001), whereas the prognosis of low-risk MDS patients did not change significantly. The improvement of survival was still measurable after exclusion of RAEB-t patients and of those, that received an allogeneic stem cell transplantation. In line with this finding, we found a lower AML progression rate in the later diagnosed group. Unfortunately, we could not identify a clear reason for this finding but rather a multifactorial cause should be assumed. As death due to bleeding complications and infections was significantly lower, an improvement of BSC may be one of the underlying causes.

Background Myelodysplastic syndromes (MDS) present with a normo- or hyperplastic bone marrow in most cases. We aimed at a characterization of patients with different types of cellularity. Methods We assessed marrow cellularity both by histology and cytology in 1270 patients and analyzed hematologic, cytogenetic, and prognostic parameters accordingly. Results The concordance of the assessment of cellularity differed dramatically between histology and cytology as only 36.5% were described as hypocellular by both methods (P

Eine Sepsis bei immunsupprimierten Patienten stellt eine besondere Herausforderung fur den Intensivmediziner dar, sowohl in der Diagnostik als auch in der Therapie. Die unzureichende bzw. fehlende Immunreaktion des Patienten auf die Bakteriamie und auf die zugrundeliegende Infektion fuhrt in der Regel zum Ausbleiben von typischen, diagnostisch wertvollen Infektionszeichen wie Infiltraten, Leukozytose oder immunserologischen Reaktionen. Auch Verlauf und Ausgang einer Sepsis werden durch ein inkompetentes Immunsystem negativ beeinflusst, demgemas tritt das Vollbild des septischen Schocks meist schnell ein und ist mit einer sehr hohen Letalitat verbunden. Hieraus resultiert fur alle beteiligten Disziplinen ein hoher zeitlicher Druck in der Einleitung aller therapeutischen Masnahmen. Meist muss eine auf Empirie basierende kalkulierte antiinfektiose Therapie ohne hinreichend verwertbare diagnostischen Hilfen durchgefuhrt werden.

Objective Patients with acute myeloid leukemia (AML) carrying FLT3-ITD mutations (FLT3-ITD+) who relapse after allogeneic 3transplantation (allo-SCT) have a very dismal prognosis with the currently available treatment options. Methods We treated 8 patients with FLT3-ITD+ AML who had relapsed in median 91 days (range, 28 – 249) following allo-SCT with a combination of the multikinase inhibitor Sorafenib and the DNA methyltransferase inhibitor Azacitidine (Aza). Results Patients received a median of 5 cycles of Aza (range, 2 to 9) and Sorafenib with a median daily dosage of 750 mg (range 400 to 800) for 129 days (range, 61 to 221). Six of 8 patients received donor lymphocyte infusions (DLI) with a median number of 2 DLI per patient (range, 1 – 4). Following this treatment 4 patients (50%) achieved a complete remission and 3 of them a complete molecular remission. Median duration of CR was 182 days (range, 158 to 406) and 2 patients remain in ongoing remission for 406 and 168 days. Median overall survival was 322 days (range, 108 to 574 days) with 3 patients being currently alive. Conclusion Taken together, the combination of Sorafenib, Aza and DLI shows promising efficacy and deserves further evaluation in larger patients groups. This article is protected by copyright. All rights reserved.

Based on centrally diagnosed 3528 patients in the Dusseldorf registry, we validated the new proposals for the classification of the MDS by the WHO working group: 256 patients were diagnosed as MDSSLD (7,3%), 978 MDSMLD (27,7%), 227 MDS RS SLD (6,4%); 321 MDS RS MLD (9,1%), 159 MDS del(5q) (4,5%), 481 MDSEB 1 (13,6%), 620 MDSEB 2 (17,6%), and 148 MDS-U (4,2%). 352 patients (16,9% of the non blastic types) changed the category, mainly moving from RCMD to MDS RS MLD, RCUD and RCMD to MDS del(5q). Median survival times of the refined groups differed from more than 60 months in the MDSSLD (RS) groups, 37 months in the MDSMLD (RS) groups, 79 months of the MDS del(5q) group and 21 and 11 months in the MDSEB 1 and 2 groups, respectively. The difference between the groups with regard to the risk of AML evolution was also impressing. No major changes were made with regard to the MDS-U categories. In summary, the proposals of the WHO group for the classification of MDS are thoughtful, taking into account biologic parameters of the diseases, a more precise wording, to some extend pragmatic and feasible.

e20550 Background: Patient selection, dosing regimens and resistance mechanisms for immune checkpoint inhibitor combination therapy remain unmet medical needs in lung cancer. Combining blockade of PD-1 and CTLA-4 can be more effective than monotherapy but is accompanied by an increase in toxicity. Thus, to circumvent unnecessary toxicity it is of great interest to identify patients who will benefit from PD-1/PD-L1 blockade alone and to add ipilimumab only in case of primary or secondary progression. We present interim data from the non-small-cell lung cancer (NSCLC) cohort of the ongoing BIOLUMA trial which evaluates efficacy and safety of nivolumab and ipilimumab in lung cancer with a broad translational program to identify potential biomarkers predictive of response and/or resistance including whole exome sequencing (WES) of serial biopsies, functional analysis of peripheral T-cells and gut microbiome analyses. Methods: BIOLUMA is a multicentre non-randomised phase II trial in 2nd line patients with non-squamous NSCLC. Patients are treated with nivolumab 240 mg until disease progression and subsequently with a combination therapy of nivolumab 3 mg/kg q2w and ipilimumab 1mg/kg q6w. Primary endpoint is overall response rate (ORR) after addition of ipilimumab to nivolumab treatment. Analysis of sequential tumor biopsies, blood and gut microbiome is performed at different timepoints. Results: To date, 26 patients have been enrolled and 9 patients were transferred to the combination therapy after progression on nivolumab monotherapy. Drop out rate between the treatment arms is high, mainly due to rapid disease progression and adverse events which don’t allow addition of ipilimumab. ORR is available for 8 of these patients: 6 patients (75%) had PD as best response, and 1 (12.5%) each had a stable disease and partial response, respectively. The patient who achieved a PR had experienced primary tumor progression on nivolumab monotherapy before. Toxicity rate was similar to what has been reported from other trials. Conclusions: In NSCLC, addition of ipilimumab to nivolumab in nivolumab refractory patients seems to be safe, but the response rate is low and the drop out between the treatment parts high. Given these data, early termination of this cohort is currently discussed. Clinical trial information: NCT03083691.

In a retrospective study, 43 patients with dysplastic neoplasms of the bone marrow (myelodysplastic syndromes and myelodysplastic/myeloproliferative-overlap neoplasms) associated with marked (grades 2-3) fibrosis were examined. Histopathologic and morphologic findings as well as cytogenetic and molecular results were correlated with clinical endpoints. Multilineage dysplasia (34 of 43 patients, 79 %) and hypercellular bone marrow (64 %) were found in most patients. In ten of 35 patients, poor risk karyotypes according to the International Prognostic Scoring System (IPSS) were recorded. The JAK2 V617F mutation was detected in four of 30 patients (13 %), and the KIT D816V mutation was found in two of 30 patients (6 %). Patients were mainly treated with palliative drugs and best supportive care. After an observation time of 1-41 (median 21) months, ten of 43 patients (23 %) had developed a secondary acute leukemia. The median survival of all 43 patients was 21.4 months (range 1.8-88.2 months). Of all prognostic parameters examined, the blast cell count at diagnosis was found to be a most reliable and most predictive marker concerning survival and leukemia progression. This confirms previous studies in dysplastic bone marrow neoplasms without fibrosis.

The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich Heine University Hospital, Dusseldorf, Germany, and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. CPSS was able to segregate patients into 4 clearly different risk groups for OS (P < .001) and risk of AML evolution (P < .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics, and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.

In 2008, the WHO proposed changes in the classification of MDS regarding RCUD and MDS unclassifiable. We validated these proposals by using 2032 patients of the Düsseldorf MDS Registry. 10% of the patients had RCUD and 6% MDS-U. Among patients with RCUD, only 9% had RN and 6% had RT. There was no correlation between dysplastic cell line and type of cytopenia. There was no difference in prognosis between RCMD and MDS-U and between RA, RT, and RN. The separation of RA, RN, and RT is not justified suggesting a consolidation as RCUD. MDS-U should be integrated into RCMD.

Patients with myelodysplastic syndromes face a poor prognosis. The exact causes of death have not been described properly in the past. We performed a retrospective analysis of causes of death using data of 3792 patients in the Dusseldorf registry who have been followed up for a median time of 21 months. Medical files as well as death certificates were screened and primary care physicians were contacted. Death after AML evolution, infection, and bleeding was considered to be clearly disease-related. Further categories of causes of death were heart failure, other possibly disease-related reasons, such as hemochromatosis, disease-independent reasons as well as cases with unclear causes of death. Median age at the time of diagnosis was 71 years. At the time of analysis, 2877 patients (75.9 %) had deceased. In 1212 cases (42.1 %), the exact cause of death could not be ascertained. From 1665 patients with a clearly documented cause of death, 1388 patients (83.4 %) succumbed directly disease-related (AML (46.6 %), infection (27.0 %), bleeding (9.8 %)), whereas 277 patients (16.6 %) died for reasons not directly related with myelodysplastic syndromes (MDS), including 132 patients with cardiac failure, 77 non-disease-related reasons, 23 patients with solid tumors, and 45 patients with possibly disease-related causes like hemochromatosis. Correlation with IPSS, IPSS-R, and WPSS categories showed a proportional increase of disease-related causes of death with increasing IPSS/IPSS-R/WPSS risk category. Likewise, therapy-related MDS were associated with a higher percentage of disease-related causes of death than primary MDS. This reflects the increasing influence of the underlying disease on the cause of death with increasing aggressiveness of the disease.

Therapies for myelodysplastic syndromes (MDS) often achieve hematological responses but their impact on overall survival has generally not been evaluated. The Duesseldorf MDS Registry allowed us to perform matched-pair analyses to assess a possible survival benefit of treatment with thalidomide, valproic acid, low-dose Ara-C, antithymocyte globulin (ATG), induction chemotherapy, or allogeneic stem cell transplantation (allo-SCT). For all treatment modalities, lengthening of survival was restricted to certain subgroups of patients. With the exception of allo-SCT, MDS treatment was generally palliative. Recently, epigenetic treatment with demethylating agents proved to be the first therapy that can significantly prolong survival in patients with higher-risk MDS.

The myelodysplastic syndromes are a heterogeneous group of disorders of the hematopoietic stem cell and stem cell niche.[1][1] The revised version of the International Prognostic Scoring System (IPSS-R), which is based on disease-related factors, was recently published.[2][2] In 2010, the MDS